PROJECT SUMMARY The goal of this proposal is to investigate the functional role of eosinophils during hepatic ischemia and reperfusion injury (IRI). Hepatic IRI is a significant source of morbidity and mortality during major hepatic resection and during liver transplantation. Previous studies have shown that following liver transplantation innate immune cells, such as neutrophils or macrophages, are activated and traffic into the hepatic allograft. Unexpectedly, we observed that eosinophils also accumulate in the liver following orthotopic liver transplantation in humans. In contrast, we could not detect any eosinophils in healthy liver biopsies. Similarly, in a murine model, eosinophils accumulate in the liver in a time-dependent fashion following hepatic IRI. Functional studies using genetic and antibody-based depletion of eosinophils demonstrate a protective role of these cells during hepatic IRI. An unbiased screen of gene expression profiles following eosinophil depletion implicated eosinophil-dependent ST2 in liver protection. Combination of genetic and adoptive transfer studies suggest that eosinophil-specific IL-33/ST2 signaling attenuates inflammation of the ischemic liver by dampening hepatic neutrophil accumulation/activation. These findings led to our hypothesis that during hepatic IRI, eosinophils protect the liver through IL-33/ST2 signaling. Three Specific Aims are proposed to i) investigate the role of eosinophils and IL-33/ST2 signaling in hepatic IRI, ii) elucidate the mechanism by which IL-33/ST2 signaling in eosinophils protects against hepatic IRI, and iii) Target IL-33/ST2 signaling in eosinophils for the treatment of hepatic IRI.